Palmitate-induced C/EBP homologous protein activation leads to NF-κB-mediated increase in BACE1 activity and amyloid beta genesis

Gurdeep Marwarha, Jared Schommer, Jonah Lund, Trevor Schommer, Othman Ghribi

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

The etiology of Alzheimer's disease (AD) is egregiously comprehended, but epidemiological studies have posited that diets rich in the saturated fatty acid palmitic acid (palmitate) are a significant risk factor. The production and accumulation of amyloid beta peptide (Aβ) is considered the core pathological molecular event in the pathogenesis of AD. The rate-limiting step in Aβ genesis from amyloid-β precursor protein (AβPP) is catalyzed by the enzyme β-site amyloid precursor protein cleaving enzyme 1 (BACE1), the expression and enzymatic activity of which is significantly up-regulated in the AD brain. In this study, we determined the molecular mechanisms that potentially underlie the palmitate-induced up-regulation in BACE1 expression and augmented Aβ production. We demonstrate that a palmitate-enriched diet and exogenous palmitate treatment evoke an increase in BACE1 expression and activity leading to enhanced Aβ genesis in the mouse brain and SH-SY5Y-APP S we cells, respectively, through the activation of the transcription factor NF-κB. Chromatin immunoprecipitation (ChIP) assays and luciferase reporter assays revealed that palmitate enhances BACE1 expression by increasing the binding of NF-κB in the BACE1 promoter followed by an enhancement in the transactivation of the BACE1 promoter. Elucidation and delineation of upstream molecular events unveiled a critical role of the endoplasmic reticulum stress-associated transcription factor, C/EBP homologous protein (CHOP) in the palmitate-induced NF-κB activation, as CHOP knock-down cells and Chop −/− mice do not exhibit the same degree of NF-κB activation in response to the palmitate challenge. Our study delineates a novel CHOP-NF-κB signaling pathway that mediates palmitate-induced up-regulation of BACE1 expression and Aβ genesis. (Figure presented.).

Original languageEnglish (US)
Pages (from-to)761-779
Number of pages19
JournalJournal of Neurochemistry
Volume144
Issue number6
DOIs
StatePublished - Mar 2018

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Keywords

  • Alzheimer's disease
  • C/EBP homologous protein
  • endoplasmic reticulum stress
  • nuclear factor of kappa-light-polypeptide gene enhancer of activated B cells
  • palmitic acid
  • β-site APP cleaving enzyme 1

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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